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Pilat, N; Klaus, C; Gattringer, M; Jaeckel, E; Wrba, F; Golshayan, D; Baranyi, U; Wekerle, T.
Therapeutic efficacy of polyclonal tregs does not require rapamycin in a low-dose irradiation bone marrow transplantation model.
Transplantation. 2011; 92(3):280-288
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Autor/innen der Med Uni Graz:
Baranyi Ulrike
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Abstract:
BACKGROUND: Mixed chimerism is an effective strategy for the induction of transplantation tolerance but the toxicity of recipient conditioning makes current bone marrow (BM) transplantation (BMT) protocols unsuitable for widespread clinical application. Therapies promoting BM engraftment under minimal conditioning would facilitate translation of this concept to the clinic. Recently, we have shown that regulatory T cell (Treg) therapy has potent engraftment-enhancing effects in an irradiation-free noncytotoxic BMT protocol, but only if it is combined with rapamycin treatment. METHODS: Here, we investigated whether polyclonal Treg therapy is effective in promoting chimerism and tolerance in an otherwise unsuccessful BMT protocol using low-dose total body irradiation (1 Gy) and costimulation blockade and determined whether Tregs do so on their own without rapamycin. RESULTS: The application of polyclonal FoxP3-transduced recipient Tregs led to durable multilineage chimerism and donor-specific skin graft tolerance whereas recipients receiving costimulation blockade alone or green flourescent protein (GFP)-transduced cells failed to develop chimerism. Infused Tregs had a limited life span as indicated by polymerase chain reaction analysis but rather contribute to de novo induction of subsequent Treg generations. Deletion of donor-reactive T cells was observed but progressed more slowly over time compared with recipients of a nonmyeloablative BMT protocol using 3 Gy total body irradiation. CONCLUSIONS: In conclusion, Treg therapy promotes BM engraftment on its own in a low-dose irradiation BMT protocol, leading to chimerism and tolerance maintained through deletional and nondeletional mechanisms.
Find related publications in this database (using NLM MeSH Indexing)
Adoptive Transfer - methods
Animals -
Bone Marrow Transplantation - methods
Female -
Green Fluorescent Proteins - genetics
Immune Tolerance - immunology
Immunosuppressive Agents - pharmacology
Mice -
Mice, Inbred BALB C -
Mice, Inbred C3H -
Mice, Inbred C57BL -
Radiation Dosage -
Sirolimus - pharmacology
Skin Transplantation - methods
T-Lymphocytes, Regulatory - drug effects T-Lymphocytes, Regulatory - radiation effects T-Lymphocytes, Regulatory - transplantation
Transplantation Chimera - immunology
Transplantation Conditioning - methods
Whole-Body Irradiation -

Find related publications in this database (Keywords)
Transplantation tolerance
Mixed chimerism
Regulatory T cells
Rapamycin
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